Individualizing Systemic Therapies in First Line Treatment and beyond for Advanced Renal Cell Carcinoma
Abstract
:Simple Summary
Abstract
1. Introduction
2. Selection of Treatment
2.1. IMDC Risk-Based Treatment Selection
2.2. Histology-Based Treatment Selection
2.3. Toxicity-Driven Treatment Selection and Modification
2.4. Consideration of Comorbidities in Treatment Selection
2.5. Assessment of Disease Distribution to Guide Treatment
2.6. Role of Genomic Markers and Biomarkers in Treatment Selection
3. Selection of Second-Line Treatment and beyond
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
ALK | anaplastic lymphoma kinase |
CCI | Charlson comorbidity index |
ccRCC | clear cell renal cell cancer |
CDCs | collecting duct carcinomas |
ChRCC | chromophobe renal cell cancer |
CR | complete response |
ctDNA | circulating tumor DNA |
CXCR4 | CXC-chemokine receptor-4 |
dBP | diastolic blood pressure |
DOR | duration of response |
EMA | European medical agency |
ESMO | European society for medical oncology |
FDA | food and drug administration |
FFS | failure free survival |
HIF | hypoxia-inducible factor |
HLRCC | hereditary leiomyomata and renal cell cancer |
ICI | immune checkpoint inhibitors |
IFN | interferon |
IL-2 | interleukin-2 |
IMDC | International Metastatic RCC Database Consortium |
ITT | intention to treat |
NCCN | national comprehensive cancer network |
ORR | objective response rate |
OS | overall survival |
PD-1 | programmed cell death-1 |
PD-L1 | programmed cell death-ligand 1 |
PFS | progression free survival |
PRCC | papillary renal cell cancer |
RCC | renal cell cancer |
RFS | relapse free survival; |
RMC | renal medullary carcinoma |
ROS1, ROS | proto-oncogene 1 receptor tyrosine kinase |
SEER | surveillance epidemiology and end results |
TKIs | tyrosine kinase inhibitors |
TMB | tumor mutational burden |
TRCC | translocation renal cell carcinoma |
TSC | tuberous sclerosis complex |
TTF | time to treatment failure |
TTR | time to treatment response |
VEGFr | vascular endothelial growth factor receptor |
VHL | Von Hippel-Lindau |
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Study | Study Type | Treatment Individualization | Treatment | Treatment Setting | Outcomes |
---|---|---|---|---|---|
Hudes et al. [20] | Prospective, randomized phase III | Clinical risk category based (Trial protocol defined poor risk group RCC) | Temsirolimus vs. IFN-a vs. Temsirolimus + IFN-a | First line | OS 10.9 vs. 7.3 vs. 8.4 months (p = 0.008) |
Checkmate 214 [21] | Prospective, randomized phase III | Clinical risk category based (IMDC intermediate- and poor-risk groups RCC) | Nivolumab + Ipilimumab vs. Sunitinib | First line | OS of 47.0 vs. 26.6 months (p < 0.0001) |
CABOSUN [22] | Prospective, randomized phase II | Clinical risk category based (IMDC intermediate- and poor-risk groups RCC) | Cabozantinib vs. Sunitinib | First line | PFS of 8.6 vs. 5.3 months (p = 0.0008) |
RESTORE [23] | Prospective, randomized phase II | Toxicity based | Standard Sunitinib schedule (4/2) vs. altered Sunitinib schedule (2/1) | First line TKI | 6-month FFS 44.0% vs. 63.0% (p = 0.029) |
Bjarnason et al. [24] | Prospective phase II | Toxicity based | Individualized Sunitinib dose and scheduled | First line | PFS 12.5 months (p < 0.001) |
PISCES [25] | Prospective, randomized phase II | Patient preference based | Pazopanib vs. Sunitinib | First line | 70% of patients favoured Pazopanib |
Gravis et al. [26] | Retrospective | Disease distribution based (Glandular metastasis vs. Non-glandular metastasis at first presentation) | Any systemic treatment | First line and beyond | OS 61.5 vs. 37.4 months (p < 0.001) |
Study | Study Type | Histology | Treatment | Outcomes |
---|---|---|---|---|
Choueiri et al [31] | Retrospective analysis | PRCC | Sunitinib vs. Sorafenib | PFS of 11.9 vs. 5.1 months (p < 0.001) |
Dutcher et al. [32] | Retrospective analysis | Non-ccRCC | Temsirolimus vs. IFN-a | OS of 11.6 vs. 4.3 months (HR 0.49; 95% CI 0.29–0.85) |
KEYNOTE 426 [33] | Prospective, randomized phase III (sub-group analysis) | RCC with sarcomatoid differentiation | Pembrolizumab + Axitinib vs. Sunitinib | PFS not reached vs. 8.4 months (HR 0.54; 95% CI 0.29–1.00) |
McKay et al. [34] | Retrospective analysis | Non-ccRCC | Monotherapy or combination PD-1/PD-L1 inhibitor | ORR 28% for PRCC 33% for translocation 43% for sarcomatoid/rhabdoid differentiation |
KEYNOTE 427 [35] | Prospective, open-label phase II | Non-ccRCC | Pembrolizumab | ORR 25.4% for PRCC 9.5% for ChRCC 34.6% for unclassified RCC |
CheckMate 214 [36] | Prospective, randomized phase III (post-hoc analyses) | RCC with sarcomatoid differentiation | Ipilimumab + Nivolumab vs. Sunitinib | ORR of 56.7% vs. 19.2% |
Oudard et al. [37] | Prospective, open-label phase II | CDCs | Cisplatin and Gemcitabine | ORR 26.0% OS of 11.0 months |
Study | Tumour Subtype | Study Type | Marker | Results, Comments |
---|---|---|---|---|
Atkins et al. [66] | ccRCC | Phase I/II study | HIF2α | CXCR4 + Axitinib delaying ± overcoming resistance to VEGFr inhibitors. |
Courtney et al. [67] | ccRCC | Phase I/II study | HIF-2α | PT2385 shows favourable safety profile and activity in patients with heavily pre-treated ccRCC. |
Srinivasan et al. [68] | ccRCC | Phase II study | HIF-2α | Improved PFS (98% at 12 months); DOR in confirmed responses NR (range 12–62 months). |
Hakimi et al. [69] | ccRCC | Single institution cohort study | PBRM1, SETD2, BAP1, KDM5C | Mutations in all genes are asssociated with advanced stage, grade, and possibly worse CSS |
Voss et al. [70] | Advanced/ metastatic RCC | Retrospective cohort study (COMPARZ and RECORD-3) | PBRM1, BAP1, TP53 | Loss of PBRM1, gain of BAP1 and/or TP53 associated with improved PFS and OS in stage IV setting |
Hsieh et al. [71] | ccRCC | Retrospective analysis (RECORD-3) | PBRM1, BAP1, KDM5C | PBRM1 and BAP1 mutations associated with longer and shorter PFS with 1L Everolimus in stage IV setting; KDM5C mutation assocaited with longer PFS with 1L Sunitinib. |
IMmotion 150 [72] | Treatment-naïve stage IV RCC | Randomized, phase II study | TMB, angiogenic gene signature | TMB and neoantigen burden not associated with PFS; angiogenesis and T-effector response strongly associated with PFS |
CREATE [73] | Type 1 PRCC | Multicentre, non-randomized, open-label phase II study | MET | Crizotinib improved PFS in MET positive/ amplified arm compared to MET negative/ non-amplified arm (80% v 22%); OS similar in both arms. |
Voss et al. [74] | Advanced/ metastatic RCC | Randomized, phase II study | PTEN | Loss of PTEN IHC expression had improved PFS when treated with Everolimus, compared to retained PTEN IHC expression (10.5 months v 5.3 months). |
Iacovelli et al. [75] Thompson et al. [76] | Advanced/ metastatic RCC | Systematic review / meta-analysis | PD-L1 | Limited utility of PD-L1 as a predictive biomarker due to the lack of negative predictive value. |
Choueiri et al. [77] | Metastatic ccRCC | Randomized, phase III study (COMPARZ) | PD-L1 | Increased PD-L1 was associated with shorter survival in patients with metastatic RCC receiving VEGFr inhibitor agents. |
IMmotion 151 [78] | Treatment-naïve stage IV RCC | Randomized, phase III study | Angiogenic gene signature, T-effector gene signature | Confirmation of angiogenesis and T-effector response strongly associating with PFS; also finding associations between angiogenesis and T-effector response, tissue subtypes, and treatment options. |
Pal et al. [79] | Stage IV RCC | Retrospective analysis | ctDNA: TP53, VHL, NF1, EGFR, PIK3CA, ARID1A | Disparity in genomic alteration frequencies in post first-line vs. first-line were in TP53 (49% vs. 24%), VHL (29% vs. 18%), NF1 (20% vs. 3%), EGFR (15% vs. 8%), and PIK3CA (17% vs. 8%) |
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Khan, Y.; Slattery, T.D.; Pickering, L.M. Individualizing Systemic Therapies in First Line Treatment and beyond for Advanced Renal Cell Carcinoma. Cancers 2020, 12, 3750. https://doi.org/10.3390/cancers12123750
Khan Y, Slattery TD, Pickering LM. Individualizing Systemic Therapies in First Line Treatment and beyond for Advanced Renal Cell Carcinoma. Cancers. 2020; 12(12):3750. https://doi.org/10.3390/cancers12123750
Chicago/Turabian StyleKhan, Yasir, Timothy D. Slattery, and Lisa M. Pickering. 2020. "Individualizing Systemic Therapies in First Line Treatment and beyond for Advanced Renal Cell Carcinoma" Cancers 12, no. 12: 3750. https://doi.org/10.3390/cancers12123750